tbuckley/cabot-search huggingface dataset:
Abstract 12521: TMEM16 Antagonists Inhibit Phosphatidylserine-Induced Procoagulant Activity in Endothelial Cells and Protect From Thrombosis in vivo
Authors: Alec A Schmaier, Papa Freduah F Anderson, Siyu F Chen, Samir M Parikh, Robert C Flaumenhaft, Sol Schulman
Journal: Circulation (2022)

Introduction: Constitutively an anticoagulant surface, endothelial cells (ECs) switch to support coagulation following pathogenic stimuli, contributing to cardiovascular disease. To promote thrombosis, coagulation proteins must assemble on a membrane surface containing the anionic phospholipid phosphatidylserine (PS). PS is asymmetrically distributed on the inner leaflet of the plasma membrane but is rapidly externalized to the outer leaflet by calcium-activated phospholipid “scramblases”, such as TMEM16F. How phospholipid externalization on ECs supports coagulation and thrombosis has not been investigated. Hypothesis: We proposed that pharmacologic inhibition of TMEM16 phospholipid scramblases inhibits EC procoagulant activity and protects against thrombosis. Methods and Results: siRNA silencing of TMEM16F, and its closest paralog, TMEM16E, inhibited factor Xa generation and thrombin generation on the EC surface (60% and 90%, respectively, p &lt; 0.0001), equivalent to the PS-binding protein lactadherin (100 nM). Two unrelated compounds with TMEM16 inhibitory activity, benzbromarone and CaCCinh-A01 (30 μM), prevented calcium-induced PS externalization on ECs, as determined by flow cytometry and immunofluorescence microscopy. These drugs did not inhibit intracellular calcium flux, suggesting they block the PS externalization activity of TMEM16. Benzbromarone and CaCCinh-A01 inhibited factor Xa generation on the EC surface in a dose-dependent manner (IC 50 3.2 μM and 2.0 μM, respectively). Thrombosis was evaluated using a laser injury model in the mouse cremasteric arteriole coupled with intravital microscopy to measure accumulation of fluorescently-labeled platelets and fibrin. Benzbromarone (5 mg/kg) inhibited platelet accumulation ( p &lt; 0.05) and fibrin formation ( p &lt; 0.01). Benzbromarone did not increase bleeding time in a tail-clip hemostasis assay. Conclusions: Activated ECs contribute anionic phospholipid to support coagulation, a process regulated by TMEM16 phospholipid scramblases. TMEM16 inhibition with benzbromarone protects from experimental thrombosis without resulting in excess bleeding. Benzbromarone is used worldwide to treat gout and could be repurposed for anti-thrombotic properties.
Abstract 11898: Bovine Milk-Derived Extracellular Vesicles as a Novel Injury-Targeting Drug Delivery System Following Cardiac Injury
Authors: Spencer R Marsh, Jane Jourdan, Robert G Gourdie
Journal: Circulation (2022)

Introduction: A novel protocol provides large amounts of highly purified small extracellular vesicles (also called exosomes) from bovine milk (Marsh et al, PMID: 34367882). We sought to examine the targeting potential of these pure, highly concentrated bovine milk-derived extracellular vesicles (mEVs) to injured cells and tissues, with the intent of identifying an effective drug delivery platform capable of targeting injured cardiac tissue. Methods: Targeting of mEVs to injured cells and tissues was tested in vitro using a scratch assay on human dermal fibroblast (hDFs) and MDCK cell monolayers, and in vivo, using mouse models of skin wounding and cardiac injury - methods we have previously reported (PMID:34246197; PMID:29351451). mEVs were isolated using our published approach (PMID: 34367882), then fluorescently tagged with Cell Tracker Deep Red (CTDR). Labelled mEVs were then applied to cell cultures at 20 ug/mL for 15 minutes post wound; cells were then rinsed, fixed and stained for cell nuclei with Hoechst. Mice were provided 2 ug/kg loaded mEV’s by oral gavage before skin surgery and induction of cardiac ischemic reperfusion injury. Mice were sacrificed 4 hours post-surgery, fixed by perfusion with 4% paraformaldehyde followed by PBS rinsing, then organs were explanted. Organs were then embedded in O.C.T, sectioned on a cryostat, and stained for nuclei and actin with FITC-Phalloidin. Imaging was performed on a Leica SP8 laser scanning confocal microscope and quantified using mEV uptake normalized to cell nuclei on ImageJ. Results: mEV uptake was significantly increased in scratch wounded cultures of both hDFs and MDCK cells (p&lt;0.001), over uninjured control cells. Similarly, injured heart and skin tissues exhibited significantly increased exosomal uptake (p&lt;0.001), relative to sham injury controls and skin tissues remote from the injury. Conclusions: Our experiments indicate that injured cells and tissues show increased uptake of milk derived exosomes, with in vitro data suggesting that this enhanced uptake occurs, at least in part, in a cell autonomous manner. The data also supports that our isolation protocol provides a novel mEV-based drug delivery system that may preferentially target injured tissues, including ischemic cardiac tissue.
Abstract 11961: Ductus Arteriosus Oxygen Response is Mediated by Mitochondrial Subunit NDUFS2
Authors: Rachel E Bentley, Charles C Hindmarch, Patricia Lima, Jeffrey Mewburn, Ashley Martin, Kimberly J Dunham-Snary, Stephen L Archer
Journal: Circulation (2022)

Introduction: The ductus arteriosus (DA) is a fetal vessel connecting the pulmonary artery (PA) and aorta, diverting oxygenated blood away from the developing lungs to the systemic circulation. The DA rapidly constricts in response to the increase in arterial oxygen (O 2 ) following the first breath. Failure of the DA to close in response to O 2 results in persistent ductus arteriosus, one of the most common complications of preterm birth. Mitochondria are known to play an important role in the O 2 response of DA smooth muscle cells (DASMC), however the mechanism is not fully understood. A subunit of mitochondrial Complex I, NDUFS2 (NADH:ubiquinone oxidoreductase core subunit 2) mediates the O 2 response of other specialized O 2 sensing tissues (PA and carotid body); we assess whether NDUFS2 also plays a role in DA O 2 sensing. Methods: DASMC were isolated from male term (29 days gestation) fetal New Zealand white rabbits. Cell lines were purified via fluorescence activated cell sorting, excluding CD90 + and CD31 + cells (fibroblasts and endothelial cells, respectively). Smooth muscle cell purity was confirmed using flow cytometry for α-smooth muscle actin (α-SMA). Primary cultures were 97.65% ± 0.65% CD90 - CD31 - , and were 100% α-SMA + post-sorting. We measured the O 2 responsiveness of DASMC using confocal microscopy, measuring changes in intracellular calcium with Cal-520AM. Cells were cultured in hypoxia (2.5% O 2 , pO 2 = 41 mmHg), with O 2 -induced increase in calcium relative to hypoxic baseline serving as a surrogate for constriction. DASMC were treated for 48 hours with 30 pmol siRNA and 90 pmol Lipofectamine® RNAiMAX to knockdown gene expression of NDUFS2 or a negative control. Knockdown was confirmed using qPCR. Results &amp; Conclusions: There was a 14.7% (±2.6%, n=33, p&lt;0.0001) increase in intracellular calcium relative to hypoxic baseline in siNC-treated cells. O 2 response was obliterated when treated with siNDUFS2 (0.7% ± 2.1%, n=29, p=0.798), with a 90.9% ± 1.89% knockdown of NDUFS2 mRNA expression. These data suggest a critical role for the mitochondrial electron transport chain, specifically NDUFS2, in DA oxygen responsiveness. While further functional studies will be required, our findings suggest a novel potential therapeutic target to modulate DA patency.
Abstract 12376: Is Supraventricular Tachycardia a Potential Complication of Bronchoscopic Lung Volume Reduction
Authors: Mohamed Abdelhabib, Daniel Rabulinski, Daniel Mayberry, Fadi Khoury, Pooja Rangan, Raed Alalawi
Journal: Circulation (2022)

Introduction: Endobronchial valve (EBV) placement is one technique to attain bronchoscopic lung volume reduction (BLVR). This procedure has shown clinical benefits in terms of lung function, symptoms, and quality of life. A few complications have been reported including pneumothorax, dislocation or migration of the valve, hemoptysis, COPD exacerbation, and pneumonia. However, supraventricular tachycardia (SVT) was not seen as a potential complication within 45 days of the procedure. Hypothesis: SVT is a complication of EBV placement to attain BLVR. Methods: We conducted a retrospective chart review of consecutive patients who underwent EBV placement between January 2018 and December 2021. Patients who developed SVT were compared to patient who did not get SVT. Results: A total of 94 cases were identified. The incidence of SVT was 18 (19.15%) cases post EBV placement. The patients who developed SVT were older (median [IQR]: 74 [69-76], 72.2% males and all were whites (100%). The time to develop SVT ranged between 2.5 hours and 118 hours with median 40.5 hours. 13 (72.2%, P= 0.007) of patients who developed SVT had an electrolyte imbalance post EBV placement. Electrolyte imbalance was an independent factor for predicting SVT on multiple regression after controlling for age, BMI, gender, and location of valve placement (adjusted OR, [CI 95%] 4.64, [1.41 - 15.29], P = 0.012). Placement of EBV in the lingula and left upper lobe (LUL) have higher incidence of SVT (5 (27.8%, P = 0.049) and 12 (66.7%, P = 0.071), respectively). Table 1 and Table 2 further summarizes the result from the study. Conclusion: Given the results, SVT can be recognized as a potential complication of BLVR. Additional caution must be paid to patients who have EBV placed in the LUL and patients with electrolyte imbalance post procedure. Electrolyte imbalance post procedure was the only statistically significant independent predicting factor for SVT. A larger study is needed to determine the level of association.
Abstract 11481: Healthcare Resource Use, Early Benefit and Cost for North American Patients With HFrEF Most Likely to Benefit from Omecamtiv Mecarbil
Authors: Nihar R Desai, Stephen J Greene, Michael Felker, Scott D Solomon, Gary Binder, Punag Divanji, Daniel R Gomes, Robb Kociol, John R Teerlink
Journal: Circulation (2022)

Introduction: In GALACTIC-HF (NCT02929329), omecamtiv mecarbil (OM) added to guideline directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) reduced the risk of composite first HF event (HFE) or CV death. Increased risk with OM use was seen in patients with both digoxin use plus atrial fibrillation/flutter (AF) together at baseline (dig+AF), but not for patients with either factor alone. A previous analysis of GALACTIC-HF found OM to reduce resource utilization and costs among higher-risk patients with EF≤30% excluding dig+AF, but the impact in the subset within North America (N Am) is unclear. Purpose: To examine resource use, timing, and HFE costs for patients treated with OM in N Am. Methods: We analyzed risk of first and total HFE (hospitalization or IV diuretic use, all adjudicated), and events at 30 days post randomization and later, for the N Am region of GALACTIC-HF. Treatment effect was evaluated in the subgroup of GALACTIC-HF previously identified as most likely to benefit from OM: EF≤30% excluding dig+AF at baseline. We applied US costs per HFE from published studies inflated to 2021 USD, including $17,123 per HF hospitalization. Results: Of 8,232 trial patients, 1,386 (16.8%) were from N Am (1,220 US), of whom 4.6% had baseline dig+AF. In the N Am subgroup of 1,090 (78.6%) with EF≤30% excluding dig+AF, OM reduced risk of first HFE vs placebo (HR 0.81, 95% CI 0.67-0.98, p=0.027); &gt;90% were hospitalizations. OM also reduced total HFE vs placebo (41.30 vs 55.46 per 100 pt-yrs, HR 0.76, 95%CI 0.61-0.94, p=0.010), with an ARR of 14.2 and a NNT of 7. Fewer HFE were seen with OM at 30 days (Incidence Rate Ratio [IRR] 0.56, p=0.035), 90 days (IRR 0.61, p=0.005) and throughout 3 yrs (IRR 0.78, p=0.029), with rising ARR. Cost reductions due to HFE avoided with OM averaged $420 / patient at 30 days, $928 at 90 days, and $6,052 (26.9% reduction) over 3 yrs. Conclusions: Among N Am patients with HFrEF≤30% and without dig+AF in GALACTIC-HF, OM significantly reduced HFEs with corresponding reductions in costs for HFEs. Clinically and statistically significant benefits were apparent within 30 days of OM initiation and continued through the trial. This large group of HFrEF patients may be where the clinical and economic benefit of OM is most evident.
Abstract 11155: Recovery of Tricuspid Valve Function After Resection of a Primary Ovarian Carcinoid Tumor
Authors: Jeffrey D Wong, Sarah D Finlayson, Jonathan D Loree, Lynn P Straatman, Parvathy Nair, Michael Y Tsang, Christina Luong, Teresa Tsang, Ken Gin, John Jue, Darwin Yeung
Journal: Circulation (2022)

Case Presentation: A 51-year-old woman presented with a &gt;1-year history of bilateral leg edema, diarrhea, and facial flushing. Examination revealed a large abdominal mass, which CT scan confirmed to be a 15x11x13 cm ovarian mass with solid and cystic components. She underwent hysterectomy and bilateral salpingo-oophorectomy. Histopathology revealed a 17 cm ovarian dermoid cyst containing an insular carcinoid tumor. Her post-operative urinary 5-hydroxyindoleacetate (HIAA) level was 23 umol/d (normal 10-40 umol/d) and chromogranin-A level was 95 ug/L (normal &lt;94 ug/L), but positron emission tomography (PET) scan showed lymph node metastasis, prompting initiation of lanreotide, a somatostatin analogue. A perioperative echocardiogram revealed thickened, fixed, and retracted tricuspid and pulmonic valves with severe tricuspid and pulmonary regurgitation consistent with carcinoid heart disease. The right ventricle was dilated but showed preserved systolic function. Valve intervention was considered but deferred as right heart catheterization 15 weeks after surgery showed normal right-sided pressures. A follow-up echo 8 months post resection showed unchanged pulmonary regurgitation but significant improvement in tricuspid valve mobility with a corresponding reduction in tricuspid regurgitation to a mild-to-moderate level. Discussion: Thickened and fixed tricuspid valve leaflets with significant regurgitation represents a hallmark of carcinoid heart disease that can lead to progressive right heart failure, often necessitating surgical intervention. This is a rare case of carcinoid heart disease where there was marked improvement in tricuspid valve function after surgical resection of a primary carcinoid tumor and initiation of somatostatin analog therapy. It highlights the potential for timely treatment to reverse the deleterious effects of carcinoid tumors on cardiac valves, which may ultimately spare the need for cardiac surgery.
Abstract 12618: Human And Mouse Demonstration Of The Reticulum-Mitochondria Ca <sup>2+</sup> Coupling As A New Therapeutic Target In Metabolic HFpEF
Authors: Maya Dia, Hala Guedouari, Juliette Geoffray, Maelle CHERPAZ, Matteo Pozzi, Christelle Leon, StÃ©phanie Chanon, Nadia Bendridi, Ludovic Gomez, Jennifer Rieusset, Helene Thibault, Melanie Paillard
Journal: Circulation (2022)

Context: Metabolic heart failure with preserved ejection fraction (HFpEF) is a frequent and disabling disease with yet no therapy and limited knowledge on the cardiac underlying molecular mechanisms. Ca 2+ transfer at mitochondria-associated reticular membranes (MAM) is crucial in the cardiomyocyte to tightly regulate mitochondrial Ca 2+ content and assure the excitation-energetics coupling. We aimed to specify the role of the MAM Ca 2+ coupling in both human and mouse hearts with metabolic HFpEF. Results: Mass spectrometry analysis of cardiac MAM showed an upregulation of cellular response to stress and lipid metabolism processes in two obesogenic T2D mouse models (16 weeks of high-fat high-sucrose diet, HFHSD vs standard diet, SD; 12-week old leptin-deficient ob/ob vs WT), while Ca 2+ transport was downregulated only in the HFHSD MAM. MAM Ca 2+ coupling assessment by adenoviral infection of a FRET-based mitochondrial Ca 2+ sensor, revealed a MAM Ca 2+ uncoupling in the HFHSD cardiomyocyte, leading to reduced mitochondrial Ca 2+ content and bioenergetics, while no change was measured in the ob/ob cell. HFHSD mice exhibited cardiac hypertrophy, diastolic dysfunction and mild strain rate reduction with preserved EF. Ob/ob mice only displayed strain rate reduction and concentric hypertrophy. Principal component analysis (PCA) demonstrated a divergence between the HFHSD group and the three others, as displayed by their scattering along the first PC (61% of variance) contributed mainly by strain rate, wall thickness, body weight and Ca 2+ peak amplitude. Proximity ligation assay revealed a decreased proximity between the reticular IP3-receptor and the mitochondrial porin VDAC in human left ventricle biopsies from T2D versus non-diabetic patients, obtained during valve replacement surgery: this suggests a reduced formation of the IP3R-driven Ca 2+ channeling complex. Conclusion: The ob/ob model does not recapitulate the main hallmarks of metabolic HFpEF and does not display any change in MAM Ca 2+ coupling. On the contrary, a MAM Ca 2+ uncoupling was detected both in the human T2D heart and in the heart of the HFHSD-induced metabolic HFpEF mouse, suggesting the reticulum-mitochondria Ca 2+ coupling as a critical therapeutic target in metabolic HFpEF.
Abstract 12463: Low-Density-Lipoprotein Cholesterol and Mortality Outcomes Among Healthy Older Adults Not Taking Lipid-Lowering Agents: A Cohort Study With 12,334 Participants
Authors: Zhen Zhou, Andrew M Tonkin, Andrea J Curtis, Anne Murray, Chao Zhu, Christopher Reid, Jeff Williamson, Joanne Ryan, John J McNeil, Lawrence J Beilin, Michael E Ernst, Nigel Stocks, Paul Lacaze, Raj Shah, Robyn Woods, Rory Wolfe, Seana L Gall, Sophia Zoungas, Suzanne Orchard, Mark R Nelson
Journal: Circulation (2022)

Introduction: Clinical uncertainty remains about the relationship between cholesterol levels and risk of death in older persons. Hypothesis: Lower low-density lipoprotein (LDL) cholesterol level was associated with a decreased mortality risk from cardiovascular disease (CVD) and an increased mortality risk due to non-CVD causes in primary prevention older populations. Methods: We examined the relationship between LDL cholesterol levels and mortality outcomes in a cohort of older individuals aged ≥65 years enrolled into a clinical trial. At baseline, participants had no diagnosed dementia, physical disability or CVD events, and were not taking lipid-lowering agents. Multivariable Cox proportional-hazards models were used to examine associations of LDL cholesterol with all-cause, CVD, cancer, and combined non-CVD/non-cancer mortality. Restricted cubic splines were used to depict non-linear relationships. Results: Among 12,334 participants included in this analysis [mean (SD) age: 75.2 (4.6) years; 54% females], who were followed for a median of 6.9 (5.7-8.0) years, 1250 (10%) died (24% due to CVD, 43% cancer, and 33% non-CVD/non-cancer). There was a U-shaped relation linking LDL cholesterol and all-cause mortality (nadir: 3.3mmol/L) and a curvilinear relation for other mortality outcomes. Each 1-mmol/L higher LDL cholesterol was associated with a lower risk of all-cause mortality (HR=0.91, 95% CI 0.85-0.98), cancer mortality (0.83, 0.74-0.94) and non-CVD/non-cancer mortality (0.81, 0.71-0.93), but a higher risk of CVD mortality (1.19, 1.03-1.38). Reduced risks of all-cause and non-CVD/non-cancer mortality were only significant in males and but not females (P values for sex interaction &lt;0.05). When deaths in the five years after baseline were excluded, the HRs for all-cause, cancer, non-CVD/non-cancer and CVD mortality were 1.03, 1.05, 0. 91 and 1.21 respectively (all P&gt;0.10). Conclusions: Higher LDL cholesterol is associated with a greater risk of CVD mortality in older adults. Reduced risks for non-CVD mortality were likely driven by reverse causality, evidenced by the absence of associations after excluding deaths that occurred within the initial five years of follow-up.
Abstract 12460: Mobile Health Access And Usage, And Cardiovascular Risk: Results From The 2017-2020 Health Information National Trends Survey (HINTS)
Authors: Yuling Chen, Ruth-Alma Turkson-Ocran, Binu Koirala, Patricia Davidson, Yvonne Commodore-Mensah, Cheryl R Dennison Himmelfarb
Journal: Circulation (2022)

Introduction: There has been a rise in the interest in mobile health technology (mHealth) to support cardiovascular (CV) health; however, the relationship between CV risk and mHealth access/usage is not clear. Methods: We used data from the 2017 to 2020 Health Information National Trends Survey. CV risk factors examined included self-reported hypertension, diabetes mellitus, physical inactivity, current smoking status, and overweight/obesity. Multivariable logistic regression models examined the association between CV risk (we defined low, moderate, and high CV risk as having 0-1, 2-3, and 4-5 risk factors, respectively) and mHealth access/usage, adjusting for age, sex, race, education, income, etc. Analyses were stratified by age &lt;65 and ≥65 years. Results: We included 16,092 adults (49% were male, 78% were aged &lt;65 years, 63% were White, 45% had annual income &lt;$50,000, 87% had at least one CV risk factor). In the full model (Table), compared to adults with low CV risk, those with moderate CV risk were more likely to use mHealth to make health decisions, OR 1.27, 95% CI (1.10-1.46), track goal progress, OR 1.22, 95% CI (1.07-1.41), share information with health providers (HP), OR 1.59, 95% CI (1.33-1.90), and discuss with HP, OR 1.27, 95% CI (1.10-1.46). Having high CV risk was associated with higher odds of mHealth access, OR 1.56, 95% CI (1.08-2.25) and using mHealth to make health decisions, OR 1.68, 95% CI (1.26-2.24), share information with HP, OR 2.55, 95% CI (1.97-3.31), and discuss with HP, OR 1.68, 95% CI (1.10-1.46). The associations remained significant among adults aged &lt;65 years. Among adults aged ≥65 years, CV risk was only significantly related to sharing information with HP. Conclusion: Younger adults with higher CV risk were more likely to access mHealth and use mHealth to make health decisions, track goal progress, share information, and aid healthcare discussions. Our findings suggest the potential of using mHealth to facilitate CV risk reduction.